Functional Characterization of Genes that Drive Hepatoblastoma
Mentor Name: Kelly Bailey
The Prochownik laboratory's Specific Aim is to determine the role of BYN genes in HB pathogenesis. Ms. Knapp will continue her ongoing work, which involves studying how BYN genes affect HB growth properties mediated by combinations of B, Y and N. Using “Sleeping Beauty” (SB) vectors that allow for gene over-expression or Crispr/Cas9 vectors that allow for gene knockout, individual BYN genes will be deregulated with transformation-competent pair-wise combinations of B, Y and N to determine how this impacts tumor growth. Preliminary results show that we can simultaneously express or knockout multiple genes, which will allow us to study BYN cooperation. Ms. Knapp has already demonstrated that the Crispr/Cas9-mediated targeting of at least four BYN genes can be effectively achieved in vivo. Longer term, HBs generated or modified by BYN genes will be studied for changes in their metabolic, biochemical and transcriptomic profiles. Ms. Knapp’s project will focus upon the continued generation and characterization of BYN SB and Crispr/Cas9 vectors, how they impact HB growth and the histologic characteristics of any resultant tumors. All pairwise and triple combinations of B, Y and N efficiently generate HBs in mice. Yet, despite their undisputed importance as oncogenic drivers, we understand virtually nothing as to which of their several thousand target genes actually drive transformation. The Prochownik lab originally identified BYN genes as the common denominators in all HBs, regardless of cause, growth rates or genetic background. The vast majority (18 of 22) are also deregulated in spontaneously arising human HBs and adult cancers where their expression levels correlate with long-term survival. 16 BYN genes are also associated with canonical Cancer Hallmarks, thus implicating them as having fundamental roles in tumorigenesis. Many BYN genes encode enzymes or extracellular/membrane-associated proteins. Gaining a better appreciation for the workings of this extremely compelling group of genes will open the door to future studies examining their function in greater detail with the intention of developing novel, BYN gene-specific targeted therapies such as enzyme inhibitors and monoclonal antibodies. This has the potential for being more effective than drugs aimed at B, Y, and/or N, which, as transcription factors, are poor targets.
